Composition and method of treating arthritis

ABSTRACT

This invention relates to the composition and method of treating arthritis, repairing of articular joint surfaces and the relief of symptoms associated with arthritis. The composition comprises a nitric oxide synthase inhibitor and amino sugars. The nitric oxide synthase inhibitor reduces the level of nitric oxide, the free radical believed responsible for the degradation of articular cartilage. Amino sugars are the building blocks of articular cartilage and have anti-inflammatory actions.

[0001] This application is a continuation-in-part of Ser. No. 09/149,241filed Sep. 9, 1998 abandoned; continuation-in-part of Ser. No.09/350,380 filed Jul. 8, 1999.

FIELD OF THE INVENTION

[0002] The present invention concerns compositions and methods oftreating arthritis, repairing of articular joint surfaces and relief ofsymptoms associated with arthritis.

BACKGROUND OF THE INVENTION

[0003] Arthritis, a musculoskeletal disorder, is the leading cause ofdisability in the United States. The Centers for Disease Control andPrevention (CDC) stated that arthritis and other rheumatic conditionsaccounted for about 744,000 hospitalizations and 4 million days of carein 1997. Forty million Americans, representing 15% of the population,have some form of arthritis, and that figure is expected to increase to59.4 million (18.2%) by the year 2020, an increase of 57% in the numberof persons affected. Arthritis patients make more than 315 millionphysician visits and are hospitalized more than 8 million times a year.Arthritis costs the nation $65 billion annually in medical costs andlost productivity. Osteoarthritis (OA), or degenerative joint disease,is the most common type of arthritis, affected 20.7 million people(12.1%) of U.S. adults in 1990, now estimated at 37 million, and trailedchronic heart disease as the leading cause of Social Security paymentsdue to long-term absence from work. Lawrence R C, et al. Arthritis &Rheumatism 1998;41:778-799.

[0004] Osteoarthritis usually presents as pain, which worsens withexercise or simply an X-ray that clearly shows thinning cartilage.Common joints affected are the knees, hips and spine, finger, base ofthumb and base of the big toe. Osteoarthritis is characterized bydegenerative changes in the articular cartilage and subsequent new boneformation at the articular margins. The primary defect in hyalinecartilage, at the articular surface of the joint, is an alteration inthe ratio of total glycosaminoglycans to that of the collagen fibercontent in the matrix. Yasuda K. Hokkaido Igaku Zasshi 1997Jul;72(4):369-76. Paleontologists have found osteoarthritis to exist inalmost every vertebrate. Joint cartilage consists of only 5 percentcells, and joint cartilage lesions do heal. Tindall W N. Business &Health Dec 1997;47-48. Bones directly underneath the cartilage injointsis called subchondral bone. This bone nourishes the cartilage withoxygen, water, and nutrients conveyed through microscopic channels. Thissupply route carries “chondroprotective agents” from the bloodstream tothe cartilage.

[0005] Cartilage is the supporting structure of the body, but has noblood vessels, nerves or lymphatics, and consists of thick bundles offibrous protein (collagen) which are woven to form the articularsurface. Proteoglycans fill the extracellular spaces not occupied bycollagen, and are a combination of protein and sugar. Each proteoglycansubunit contains a protein core attached to hundreds of long chains ofspecially modified sugars called glycosaminoglycans (GAGS). Glucosamineis the single most important component and precursor for GAGs.Glucosamine is almost completely absorbed by the GI tract into thebloodstream. Cartilage rebuilding is only as good as its GAG synthesis.Chondrocytes in the cartilage obtain glucosamine from the subchondralblood vessels and manufacture N-acetylglucosamine (NAG) and glucuronicacid, which make hyaluronan, which is half glucosamine, and provides thelubricating ability of joints.

[0006] There is no definitive answer regarding the cause ofosteoarthritis. A natural erosion of cartilage occurs with age, butexcessive loads placed on joints, obesity, heredity, trauma, decreasedcirculation, poor bone alignment, and repetitive stress motion play arole. Osteoarthritis may also be the result of free radical damage,thought to be a major cause of many diseases, including the agingprocess, cancer, heart disease and degenerative diseases.

[0007] Free radicals affect the immune system causing rheumatoidarthritis and osteoarthritis. Free radicals are atoms or atomic groupsthat are byproducts of normal metabolism, tobacco smoke, pollutants, carexhaust, bacteria, radiation, and chemicals which oxidize or damageotherwise healthy cells. They damage DNA, corrode cell membranes, andmay play a role in the development of cancer, heart and lung disease,cataracts, and cause or accelerate the aging process. Bucci wrote thatthere is conclusive evidence that free radicals do most of their damagein rheumatoid arthritis, but also to the cartilage in osteoarthritis.Bucci L. Healing Arthritis the Natural Way Arlington, Tex.: SummitPublishing Group, 1995, pp. 34-5. In his best seller, Theodosakis statedthat “Osteoarthritis may be the result of free radical damage. And tomake matters worse, joint inflammation itself may trigger an even fasterrate of new free radical formation. Prevention of free radical damage isa critical feature in treating and preventing osteoarthritis.”Theodosakis J, Adderly B, Fox B. The Arthritis Cure New York, St.Martin's Press, 1997, p 147-9. Unless the damage caused by free radicalformation is addressed, any benefits obtained by using onlychondroprotective agents could be nullified; similar to trying to fill asieve with water, the relief is transient but pathology progresses.

[0008] There is no known drug that claims to reverse osteoarthritis.Most therapeutic agents are directed at reducing the inflammation andrelieving pain. Non-steroidal anti-inflammatory drugs (NSAIDs) are thefirst line of treatment for osteoarthritis, but long-term use can leadto gastric ulcers, kidney damage, hearing loss and even inhibitcartilage formation.

SUMMARY OF THE INVENTION

[0009] This invention relates to the composition and method of treatingarthritis, repairing of articular joint surfaces and the relief ofsymptoms associated with arthritis. The nitric oxide synthase inhibitorreduces the level of nitric oxide, the free radical responsible for thedegradation of articular cartilage. Amino sugars are the building blocksof articular cartilage and have anti-inflammatory actions.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] Osteoarthritis is thought to be the result of decreasedproduction and increased degradation of the cartilaginous matrix. Lossof this protective layer leads to roughening and fissuring of thecartilage and may eventually cause erosion severe enough to expose thebone. The current goal of osteoarthritis therapy is the relief of pain.NSAID use is limited by the fact that they do not change the naturalcourse of the disease and may accelerate joint deterioration in the longrun.

Nitric Oxide Synthase Inhibitors

[0011] The maintenance of articular cartilage requires a balance betweenanabolic and catabolic processes. An increase in some cytokines, such asinterleukin-1 (IL-1), is associated with a decrease in the synthesis andincrease in the degradation of proteoglycans and collagens necessary forthe structural integrity of the cartilaginous matrix. While cytokines,such as transforming growth factor β (TGF β), stimulates chondrocytesynthesis of collagens and proteoglycans, reduces the activity ofIL-1-stimulated proteinases, and opposes the inhibitory and cataboliceffects of IL-1.

[0012] Patients presenting with either rheumatoid arthritis (RA) orosteoarthritis (OA) have been observed to have increased levels of NO inthe synovial fluid. A significant source of NO production in thesepatients appeared to be articular chondrocytes. Henrotin Y E, et al,Nitric oxide downregulates cytokines, J of Rheumatology1998;25(8):1595-1601. Nitric oxide (NO) is produced by articularchondrocytes in large amounts for extended periods of time by aninducible form of nitric oxide synthase (NOS) in response to activationby IL-1 and other agents. An increase in NO decreases the synthesis ofproteoglycans and type II collagen. If NO production is blocked with theuse of N^(G)-monomethyl-L-arginine (L-NMA), an inhibitor of NOS,inhibition of proteoglycan synthesis by IL-1β is blocked, andconcentration of TGF β is increased. Studer R K, Georgescu H I, Miller LA, Evans C H, Inhibition of transforming growth factor β production bynitric oxide-treated chondrocytes, Arthritis & Rheumatism1999;42(2):248-257.

[0013] Nitric oxide is a short lived, gaseous free radical that issynthesized from the terminal guanidino nitrogen of L-arginine in anoxidation reaction catalyzed by NOS. NOS expression is inducible byendotoxin, cytokines, growth factor and immune complexes. Theoverexpression of NOS in rheumatoid arthritis (RA) may result fromincreased levels of tumor necrosis factor-α (TNF-α), IL-1β, and otherproinflammatory cytokines characteristic of this disease. Chondrocytesfrom patients with OA and RA spontaneously over express NOS and produceelevated levels of NO. St. Clair E W, Nitric oxide—friend or foe inarthritis? J of Rheumatology 1998;25(8):1451-1453.

[0014] Canadian researchers reduced the progression of experimentalosteoarthritis in dogs by inhibiting inducible nitric oxide synthase(NOS). Pelletier J P, et al. Arthritis & Rheumatism1998;41:1275-1286.Pelletier reported that osteoarthritis cartilage produced an increasedamount of nitric oxide (NO) due to an increased level of induciblenitric oxide synthase in cartilage chondrocytes. Nitric oxide plays animportant role in autoimmunity and inflammation. Normal cartilage doesnot produce NO or express NOS unless stimulated with cytokines. In thejoint, NO, produced in response to cytokine stimulation, exerts a numberof catabolic effects on chondrocyte functions which would be expected topromote the degradation of articular cartilage. These effects of NO onchondrocytes include: inhibition of collagen and proteoglycan synthesis,activation of metalloproteinases, increased susceptibility to injury byother oxidants, inhibition of actin polymerization, and apoptosis.NSAIDs, such as aspirin, and to a lesser extent, sodium salicylate, andtetracycline inhibit the expression of NOS protein. Clancy R M, Amin AR, Abramson S B. Arthritis & Rheumatism 1998;41:1141-1151.

[0015] Nitric oxide synthase inhibitors which may be employed include,but are not limited to: arginine-based analogues such as methylatedarginines, substituted L-arginine, nitro-arginine,L-N^(G)-nitroarginine, N^(G)-mono-methyl-L-arginine (NMA),N-nitro-L-arginine methyl ester, N-amino-L-arginine,N-methyl-L-arginine, N^(G)-monomethyl-L-arginine (L-NMA),L-N^(G)-mono-methyl-arginine (L-NMMA); flavoprotein binders such asdiphenylene iodonium and related iodonium derivatives, ornithine andornithine derivatives such as N-imino-ethyl-L-ornithine; tetracycline;L-canavanine; citrulline; redox dyes such as methylene blue; calmodulinbinders such as trifluoropiperazine and calcinarin; heme binders; zinccompounds; tetrahydropterin analogs such as aminoguanidine; anddepleters of biopterin such as methotrexate.

[0016] The use of NOS inhibitors is well known in the art. Dawson et al,U.S. Pat. No. 5,266,594, discloses a method of preventing or treatingglutamate neurotoxicity with a NOS inhibitor capable of penetrating theblood brain barrier. Ahluwalia et al, U.S. Pat. No. 5,468,476, disclosesa method of reducing hair growth with a NOS inhibitor. Wahl et al, U.S.Pat. No. 5,449,688, discloses a method for treating chronic inflammatoryconditions by parenterally or intravenously administering a NOSinhibitor. Stamler et al, U.S. Pat. No. 5,545,614, discloses a methodfor stimulating skeletal muscle contractions with a NOS inhibitor.Moncada et al, U.S. Pat. No. 5,585,402, discloses a method forinhibiting tissue damage by using a NOS inhibitor to decrease NOproduction in vascular endothelial cells. Dunn et al, U.S. Pat. No.5,665,757, discloses a method for treating anxiety using a NOSinhibitor. Mjalli et al, U.S. Pat. No. 5,723,451, discloses a method forinhibiting NOS using one of eleven formulations. None of the above citedpatents teach or suggest the use of the composition and method outlinedin the present invention.

Amino Sugars

[0017] Agents that may repair, or at the very least, slow thedegradation of articular cartilage have been described as possessingchondroprotective properties. Examples of these agents include:heparinoids (Arteparon, Rumalon), hyaluronic acid, piroxicam,tetracyclines, corticosteroids, chondroitin, and glucosamine sulfate. DaCamara C C, Dowless G V. Annals of Pharmacotherapy 1998;32:580-7.

[0018] Glucosamine from exogenous sources (food and supplements) maystop the progression of cartilage degradation and stimulate theproduction of new cartilage. Glucosamine absorbed by thegastrointestinal tract undergoes significant first-pass metabolism inthe liver, with the resulting 26% bioavailibility. It is incorporatedinto plasma proteins as a result of hepatic metabolism, and concentratesin the articular cartilage. Clinical improvement of symptoms has beenseen as early as one week after oral administration of glucosaminesulfate and has persisted for up to four weeks after discontinuation.Barclay T S, Tsourounis C, McCart G M. Glucosamine. Annals ofPharmacotherapy 1998;32:574-79.

[0019] Several commercial forms of glucosamine are available, includingthe sulfate, hydrochloride, and N-acetylglucosamine (NAG). Glucosaminehydrochloride has a higher concentration of glucosamine than the sulfateform. NAG is rapidly metabolized to make proteins and provides lessglucosamine for cartilage repair. The composition of the invention couldinclude one or a combination of the glucosamine forms. Patients havereported a more rapid response with higher dosages of glucosamine, butthe therapeutic results with glucosamine alone have not been consistent.The dosage range for glucosamine can vary from 500 mg to 3000 mg a day,in divided doses, depending on body weight and severity of symptoms. Oneapproach is to take 1,500 mg of glucosamine daily until symptoms havedecreased, then reduce the dosage to 1,000 mg for two weeks andeventually stop treatment after symptoms cease or stay on a maintenancedose of 500 mg per day.

[0020] Adverse effects reported from glucosamine are gastrointestinal,such as heartburn and epigastric pain. Because the half-life ofglucosamine in the blood is relatively short, a sustained-release formof the compound could avoid the adverse effects and provide a moreuniform blood level. Talent J M, Gracy R W. Clinical Therapy1996;18(6):1184-90.

[0021] The use of amino sugars is well known in the art. Jacobi, U.S.Pat. No. 3,859,436, discloses a topical composition of glucose,fructose, glucosamine and desoxyribose and ribose. Prudden, U.S. Pat.No. 4,006,224, discloses a method for treating inflammatory disorders ofthe gastrointestinal tract with D-glucosamine. Meisner, U.S. Pat. No.4,590,067, discloses a composition for the prevention and treatment ofperiodontal disease comprising, bone meal, tyrosine, glucosamine andascorbic acid. Speck, U.S. Pat. No. 4,870,061, discloses a method fortreating degenerative joint disease by buccal administration ofN-acetylglucosamine. Kludas, U.S. Pat. No. 5,036,056, discloses a methodfor treating damaged connective tissue with a connective tissue matrixof collagens, proteoglycans, glycosaminoglycans and glycoproteins.Henderson, U.S. Pat. Nos. 5,364,845 and 5,587,363, discloses acomposition for the repair of connective tissue comprising glucosamine,chondroitin sulfate and manganese. Williams et al, U.S. Pat. No.5,679,344, discloses a composition for articular disorders comprisingglucosamine and proteases. Diaz et al, U.S. Pat. Nos. 5,795,576 and5,891,441, discloses a composition and method for the elimination ofundigested fat prior to digestion comprising, psyllium, glucosamine,glucomannan, apple pectin and stearic acid. Murad, U.S. Pat. No.5,804,594, discloses an oral composition for improving skin conditionscomprising, N-acetylglucosamine, ascorbic acid, amino acids, and atransition methal composition. Florio, U.S. Pat. No. 5,840,715,discloses a composition of nutritional supplements of gamma linolenicacid, eicosapentaenoic acid and docosahexaneoic acid, chondroitinsulfate, N-acetylglucosamine sulfate, glucosamine sulfate and manganeseaspartate. Platt, U.S. Pat. No. 5,891,861, discloses a composition ofoligomers of beta glucosamine to treat fungal diseases. Weisman, U.S.Pat. No. 5,888,514, discloses a composition of natural ingredients fortreating bone and joint inflammation usingshark cartilage, glucosamine,herbs and enzymes. None of the above cited patents teach or suggest thecomposition or method outlined in the present invention.

[0022] Chondroitin sulfate is the major GAG in cartilage, and has asynergistic effect with glucosamine, but poorly absorbed by oraladministration. Chondroitin sulfate is half galactosamine, which is madedirectly from glucosamine, and has great water retaining ability. Dosagerange of chondroitin sulfate is 250 mg to 1,000 mg per day in divideddoses. Morrison, U.S. Pat. No. 3,895,107, discloses a method ofinhibiting atherosclerotic lesions by administering chondroitin sulfate.Walton et al, U.S. Pat. No. 4,489,065, discloses the binding of drugs tochondroitin for the controlled release of the drug. None of the abovecited patents teach or suggest the use of the composition and methodoutlined in the present invention.

Zinc Compounds

[0023] Zinc plays a physiological role in the regulation of bonemetabolism, by stimulating bone formation and mineralization and aninhibitory effect on bone resorption. Zinc activates aminoacyl-tRNAsynthetase in osteoblastic cells, stimulates cellular protein synthesis,and inhibits osteoclast-like cell formation in marrow cells. Bone zinccontent is decreased by development, with aging, skeletal unloading, andpostmenopausal conditions. Zinc plays a role in the preservation of bonemass. Most zinc compounds, such as zinc sulfate, are useful for theprevention of osteoporosis, but a recent study confirmed thatβ-Alanyl-L-histidinato zinc (AHZ) has a potent effect on bone formationand calcification. Yamaguchi M, Role of Zinc in Bone Formation and BoneResporption, J. of Trace Elements and Experimental Medicine1998;11:119-135.

[0024] Zinc compounds have anti-inflammatory and anti-infectiveproperties. In a recent published article, Petrus E J et al., CurrentTherapeutic Research, 1998;59/9:595-607, the inventor served as chiefinvestigator for a randomized, double-masked, placebo-controlledclinical study of the effectiveness of zinc acetate lozenges on commoncold symptoms in allergy-tested subjects. Those subjects who used thezinc lozenges had both a shorter duration and severity of common coldsymptoms. Those subjects who were positive for allergies, were moreresponsive to zinc by having a shorter duration of nasal symptoms. Thestudy cited many references that reported the benefits and effects ofzinc compounds.

[0025] Zinc is an essential mineral found in every form of life onearth. Unlike other metals, zinc is virtually nontoxic. Zinc and itscompounds have long been recognized as possessing certain therapeuticfunctions. Zinc compounds are acknowledged as astringents and beneficialin wound healing, reducing inflammation, and has antimicrobial,antifungal and antiviral activity. Zinc is the active agent informulations to treat diaper rash, decubitus ulcers, and abrasions. Zincstabilizes the cell membranes and inhibits the formation of freeradicals. Zinc also strengthens the integrity of blood vessel walls byreducing the membrane permeability and stopping bleeding.

[0026] Zinc has an inhibitory effect on the release of histamine frommast cells due to its stabilizing effect of the mast cell membrane. Mastcells isolated from specimens of atherosclerotic plaques containedmatrix metalloproteinase type 9, one of the enzymes that can producecollagen degradation. Kovanen Pt, et al. J. Am College of Cardiology1998;32:606-612. The inhibitory effect of zinc on allergy and immunologymake it an excellent enhancement to glucosamine and chondroitin therapy.Zinc is also a very potent inhibitor of nitric oxide synthase (NOS).Cuajungco M P, Lees G J Neurobiol Disease 1997;4(3-4):137-69.

[0027] In a preferred form of the invention, the composition uses a zincsalt such as zinc acetate, with the dosage range of 30 to 60 mg per dayin divided doses. Zinc salts are selected from a group consisting of,but not limited to: zinc sulfate, zinc chloride, zinc acetate, zincphenol sulfonate, zinc borate, zinc bromide, zinc nitrate, zincglycerophosphate, zinc benzoate, zinc carbonate, zinc citrate, zinchexafluorosilicate, zinc diacetate trihydrate, zinc oxide, zincperoxide, zinc salicylate, zinc silicate, zinc stannate, zinc tannate,zinc titanate, zinc tetrafluoroborate, zinc gluconate, and zincglycinate.

[0028] Zinc acetate is absorbed throughout the small intestine and hasan excellent safety profile. It does not adversely alter serum albumin,bilirubin, aminotransferases, hematologic variables, iron metabolism orrenal function indices. Zinc acetate has been assigned to FDA pregnancycategory A, indicating that the possibility of fetal abnormalitiesappears remote. In several trials, no toxic adverse effects have beenreported in any patient. The most common adverse effect of zinc therapyis gastrointestinal irritation, which is reported to occur inapproximately 10% of patients. Anderson L A, Hakojarvi A L, Boudreaux SK. Annals of Pharmacotherapy 1998;32:78-87. A controlled-releaseformulation could reduce GI irritation and enhance absorption.

[0029] Although any suitable route of administration may be employed forproviding the subject with an effective dosage of the compositionaccording to the methods of the present invention, oral administrationis preferred. Suitable routes include, for example, oral, rectal,parenteral, intravenous, topical, transdermal, subcutaneous,intramuscular, and like forms ofadministration may be employed. Suitabledosage forms include tablets, troches, dispersions, suspensions,solutions, capsules, patches, suppositories, creams, ointments, gels,and the like, although oral dosage forms are preferred. A topicalcomposition, with a permeation enhancing amount of at least onepenetration enhancer, in an appropriate pharmaceutical carrier, could bein the form of a gel, ointment, cream, solution or other means.

Enteric Coating

[0030] The use of pharmaceutical controlled release methods to deliverthe composition to the gastrointestinal tract with a desired level ofnitric oxide synthase inhibitors, amino sugars and other agents withoutthe adverse gastrointestinal effects is well known in the art.

[0031] Enteric coatings are pH sensitive polymers designed to remainintact in the acidic environment of the stomach, but to dissolve in themore alkaline environment of the intestine. Some enteric coatings useblends of cellulose acetate phthalate polymers. Wu et al, U.S. Pat. No.5,356,634 discloses an enteric coating composition of cellulose acetatephthalate (CAP) and cellulose acetate trimellitate polymers. Crook etal, U.S. Pat. No. 5,723,151 discloses a composition of cellulose acetatephthalate polymer and organic solvent. Some enteric coatings usepolyvinylpyrrolidone (PVP). Sipos, U.S. Pat. No. 4,079,125 discloses abinder and stabilizer of PVP and a coating of CAP and diethyl phthalate.Patell, U.S. Pat. No. 4,775,536 discloses the use of an enteric polymerof an acrylic resin and an undercoat and overcoat of PVP. Hodges et al,U.S. Pat No. 5,225,202 discloses an enteric coated composition ofhydroxypropylmethyl cellulose phthalate, a plasticizer of triethylcitrate and talc as an anti-adherent.

[0032] Some polymers commonly used for enteric coatings are celluloseacetate phthalate (CAP), hydroxypropyl methylcellulose phthalate(HPMCP), cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose acetate succinate (HPMCAS), polyvinyl acetate phthalate(PVAP) and acrylic resins. One formulation of the present invention uses7 mg of polyvinylpirrolidone to coat the immunostimulant composition.The composition can be in the form of a tablet, capsule, granules, orpill for oral administration. Disintegration of the PVP enteric coatingoccurs in approximately 40 minutes, about the time the composition is inthe intestine.

[0033] In addition to nitric oxide synthase inhibitors and amino sugars,the following active agents may supplement the composition to promotethe development and maintenance of cartilage, include but are notlimited to: vitamins, A, B, C, E; minerals, selenium, silica, manganese,magnesium, copper and boron; glycosaminoglycans; analgesics,anti-inflammatory agents, methyl-sulfonyl-methane,S-adenosyl-methionine, alpha-lipoic acid, aloe vera extract,preservatives, antioxidants, stabilizers, surfactants, anti-infectiveagents, adjuvants, anthocyanidins, proanthocyanidins, and herbalderivatives.

[0034] In a further aspect of this invention, for those who havedifficulty swallowing a large tablet, due to esophageal strictures orother pathology, a therapeutically effective solution can beadministered by a suspension of the active agents in a pharmaceuticallyacceptable carrier to provide a liquid form to be swallowed or sprayedonto the oral mucosa. By a “pharmaceutically acceptable carrier” ismeant a composition, solvent, dispersion medium, coating, deliveryvehicle or the like, which can be employed to administer thecompositions of the present invention without undue adversephysiological effects.

[0035] Although illustrative embodiments of the invention have beenshown and described, a wide range of modifications, change, andsubstitution is contemplated in the foregoing disclosure and in someinstances, some features of the present invention may be employedwithout a corresponding use of the other features. Accordingly, it isappropriate that the appended claims be construed broadly and in amanner consistent with the scope of the invention. The above-mentionedpatents are hereby incorporated by reference.

[0036] This invention is further illustrated by the following exampleswhich are to be regarded as illustrative only, and in no way limit thescope of the invention.

EXAMPLE 1

[0037] A 58 year old male with diagnosed osteoarthritis of both kneeswas started on a commercial composition of glucosamine hydrochloride 500mg and chondroitin sulfate 400 mg taken three times a day for sixmonths. The relief from pain and limitation of motion was inconsistent.A new composition, of the invention, comprising zinc acetate 20 mg andglucosamine sulfate 500 mg coated with polyvinylpirrolidone 7 mg takenthree times a day was commenced. By the 21^(st) day of treatment withthe new formulation, the knee pain subsided and range of motion wasunrestricted. A maintenance dose of glucosamine sulfate 500 mg and zincacetate 10 mg was then continued for six months and the pain relief andrange of motion of the knees were maintained.

EXAMPLE 2

[0038] A 59 year old male with diagnosed osteoarthritis of the rightfoot with severe pain on running. He started on a commercial compositionof a glucosamine complex (glucosamine hydrochloride, N-Acetylglucosamineand glucosamine sulfate) 500 mg and chondroitin sulfate 400 mg, takenthree times a day for three months. The pain relief was inconsistent andrequired supplemental analgesics in order to obtain relief. A newcomposition, of the invention, comprising zinc acetate 20 mg andglucosamine sulfate 500 mg coated with polyvinylpirrolidone 7 mg takenthree times a day was commenced. By the second week of treatment withthe new formulation, the foot pain subsided and he was able to run andresume his tennis playing. A maintenance dose of glucosamine sulfate 500mg and zinc acetate 10 mg was then continued for five months and thepain relief and ability to run and play sports continued.

EXAMPLE 3

[0039] A 12 year old Weimaraner developed weakness of his hind legswhich limited his ability to jump and lift his leg to urinate. He wasevaluated by the College of Veterinary Medicine at Texas A&M Universityand started on prednisone 20 mg per day but with limited success. He wasthen started on the new composition, of the invention, comprising zincacetate 20 mg and glucosamine sulfate 500 mg coated withpolyvinylpirrolidone 7 mg taken twice a day. After three weeks oftreatment with the new formulation, he demonstrated increased strengthof his hind legs and regained his ability to lift his leg on urinatingand no pain on deep palpation of the hips. He was then maintained onglucosamine sulfate 500 mg and zinc acetate 10 mg, twice a day for 11months until his death. While on the maintenance dose he continued todemonstrate strength in his hind legs.

[0040] Although illustrative embodiments of the invention have beenshown and described, a wide range of modifications, change, andsubstitution is contemplated in the foregoing disclosure and in someinstances, some features of the present invention may be employedwithout a corresponding use of the other features. Accordingly, it isappropriate that the appended claims be construed broadly and in amanner consistent with the scope of the invention.

What is claimed is:
 1. A method for treating arthritis in mammals byadministering a therapeutically effective amount of a compositioncomprising: a) an inhibitor of nitric oxide synthase, and b) anaminosugar.
 2. The method of claim 1, wherein said aminosugar in thecomposition is selected from the group consisting of: glucosamine,glucosamine hydrochloride, glucosamine sulfate, N-acetylglucosamine andmixtures thereof.
 3. The method of claim 1, wherein the compositionoptionally contains additional agents selected from the group consistingof: glycosaminoglycans, vitamin A, vitamin B, vitamin E, selenium,silica, manganese, magnesium, copper, boron, analgesics,anti-inflammatory agents, methyl-sulfonyl-methane,S-adenosyl-methionine, alpha-lipoic acid, aloe vera extract,antioxidants, anti-infective agents, adjuvants, anthocyanidins,proanthocyanidins, and herbal derivatives, and mixtures thereof.
 4. Themethod of claim 1, wherein said composition has an enteric coating todeliver the composition orally in a controlled release into thegastrointestinal tract.
 5. The method of claim 1, wherein thecomposition further comprises a carrier suitable for oral, rectal,parental, intravenous, topical, transdermal, subcutaneous, andintramuscular administration.
 6. The method of claim 1, wherein saidinhibitors of nitric oxide synthase include zinc compounds, argininederivatives, flavoprotein binders, diphenylene iodonium and derivativesthereof, ornithine and derivatives thereof, N-imino-ethyl-L-ornithine,tetracycline, L-canavanine, citrulline, redox dyes, methylene blue,calmodulin binders, trifluoropiperazine, calcinarin, heme binders,tetrahydropterin derivatives, aminoguanidine, depleters of biopterin,methotrexate, nonsteroidal anti-inflammatory agents, sodium salicylate,and mixtures thereof.
 7. The method of claim 6, wherein said argininederivitives include methylated arginines, substituted L-arginine,nitro-arginine, L-N^(G)-nitroarginine, N^(G)-monomethyl-L-arginine(NMA), N-nitro-L-arginine methyl ester, N-amino-L-arginine,N-methyl-L-arginine, N^(G)-monomethyl-L-arginine (L-NMA),L-N^(G)-monomethylarginine (L-NMMA).